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Principal Investigator: Maciej Walczak
Organization: UNIVERSITY OF COLORADO
Fiscal Year: 2024
Award: $302,384
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY/ABSTRACT
Antibiotics have transformed the human health and disease landscape. However, the use and
misuse of such antimicrobial drugs accelerate the emergence of bacterial strains resistant
against antibiotics, so that standard treatment options eventually become ineffective. In light of
these critical needs, thiopeptides have emerged as a promising platform for the discovery of
new therapeutic leads. In Aim 1, we will develop and optimize the preparation of 26-membered
thiopeptides by inventing a new cyclodehydration methods to facilitate the synthetic campaign.
The methods established in this aim will be validated in the context of representative
azole/azoline-containing antimicrobial peptides. In Aim 2, we will optimize a streamlined
synthesis of 35-membered thiopeptides by integrating Mo-catalyzed cyclodehydrations and site-
selective Dha mutations. These findings will unlock the translational potential of a previously
unexplored class of potent antibiotics. In Aim 3, we will develop an automated platform for
rational thiopeptide design and modifications, and integrate it with microbiological, biophysical,
and computational studies to generate promising leads suitable for pre-clinical and clinical
investigations. Successful realization of the abovementioned aims will establish innovative tools
for the synthesis of thiopeptides and other bioactive macrocyclic peptides. Because of the
importance of azol(in)es as the key structural elements in bioactive natural products of
biomedical relevance, the discoveries of this study will have a transformative impact on the
development of new therapies.
Terms: <Acceleration><Anabolism><Anti-Bacterial Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Azoles><Bacteremia><Bacteria resistance><Bacteria resistant><Bacterial resistant><Behavior><Binding><Biological><Biology><Biophysics><Chemicals><Clinical Research><Clinical Study><Cognitive Discrimination><Data><Death Rate><Development><Discrimination><Disease><Disorder><Drug Design><ESKAPE><ESKAPE pathogens><Elements><Engraftment><Enzyme Gene><Enzymes><Evaluation><Genes><Genetic Alteration><Genetic Change><Genetic defect><Goals><Gram-Positive Bacteria><Health><Health Care Systems><Healthcare Systems><Human><Investigation><Knowledge><Lead><Light><MRSA><Medicinal Chemistry><Methicillin Resistant S. Aureus><Methods><Microbiology><Miscellaneous Antibiotic><Modality><Modern Man><Modification><Molecular Interaction><Molecular Target><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Mutation><Oxazoles><Pb element><Peptides><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmacology><Photoradiation><Preparation><Property><Proteins><Research><Resistance><Resistance development><Resistance profile><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant development><Resistant profile><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Ribosomes><Role><Site><Solubility><Source><Structure-Activity Relationship><Tail><Testing><Therapeutic><Thiazoles><Treatment Protocols><Treatment Regimen><Treatment Schedule><Validation><anti-bacterial><anti-microbial><anti-microbial agent><anti-microbial drug><anti-microbial peptide><anti-microbial resistant pathogen><antimicrobial><antimicrobial resistant pathogen><aqueous><bacteraemia><bacterial resistance><bacterial sepsis><bactericidal><bactericide><bioactive natural products><biologic><biophysical analysis><biophysical foundation><biophysical principles><biophysical sciences><biophysical studies><biosynthesis><candidate identification><catalyst><chemical structure function><clinical investigation><combat><computational studies><computer based prediction><computer studies><covalent bond><dehydroalanine><design><designing><developing resistance><developmental><drug discovery><economic cost><flexibility><flexible><genome mutation><heavy metal Pb><heavy metal lead><improved><innovate><innovation><innovative><invention><member><methicillin resistance Staphylococcus aureus><methicillin resistant Staphylococcus aureus><methicillin resistant strains of Staphylococcus aureus><mortality rate><mortality ratio><multi-drug resistant><multidrug resistant><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathogen><pre-clinical><pre-clinical study><preclinical><preclinical study><predictive modeling><preparations><resistance strain><resistance to Bacteria><resistance to Bacterial><resistant><resistant strain><resistant to Bacteria><resistant to Bacterial><small molecule><social role><standard care><standard treatment><structural biology><structure function relationship><timeline><tool><translational opportunities><translational potential><validations>